Cai Jiangxia, Chen Siying, Zhang Weipeng, Zheng Xiaowei, Hu Sasa, Pang Chengsen, Lu Jun, Xing Jianfeng, Dong Yalin
Department of Pharmacy, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, PR China; Department of Pharmacy, The People's Hospital of Bayingol Mongolian Autonomous Prefecture, Korla, Xinjiang 841000, PR China.
Department of Pharmacy, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, PR China.
Phytomedicine. 2014 Oct 15;21(12):1725-32. doi: 10.1016/j.phymed.2014.08.007. Epub 2014 Sep 17.
Chemotherapy resistance represents a major problem for the treatment of patients with breast cancer and greatly restricts the use of first-line chemotherapeutics paclitaxel. The purpose of this study was to investigate the role of transgelin 2 in human breast cancer paclitaxel resistance cell line (MCF-7/PTX) and the reversal mechanism of salvianolic acid A (SAA), a phenolic active compound extracted from Salvia miltiorrhiza. Western blotting and real-time quantitative polymerase chain reaction (qRT-PCR) indicated that transgelin 2 may mediate paclitaxel resistance by activating the phosphatidylinositol 3-kinase (PI3 K)/Akt signaling pathway to suppress MCF-7/PTX cells apoptosis. The reversal ability of SAA was confirmed by MTT assay and flow cytometry, with a superior 9.1-fold reversal index and enhancement of the apoptotic cytotoxicity induced by paclitaxel. In addition, SAA effectively prevented transgelin 2 and adenosine-triphosphate binding cassette transporter (ABC transporter) including P-glycoprotein (P-gp), multidrug resistance associated protein 1 (MRP1), and breast cancer resistance protein (BCRP) up-regulation and exhibited inhibitory effect on PI3 K/Akt signaling pathway in MCF-7/PTX cells. Taken together, SAA can reverse paclitaxel resistance through suppressing transgelin 2 expression by mechanisms involving attenuation of PI3 K/Akt pathway activation and ABC transporter up-regulation. These results not only provide insight into the potential application of SAA in reversing paclitaxel resistance, thus facilitating the sensitivity of breast cancer chemotherapy, but also highlight a potential role of transgelin 2 in the development of paclitaxel resistance in breast cancer.
化疗耐药是乳腺癌患者治疗中的一个主要问题，极大地限制了一线化疗药物紫杉醇的使用。本研究的目的是探讨凝溶胶蛋白2在人乳腺癌紫杉醇耐药细胞系（MCF-7/PTX）中的作用以及丹参中提取的酚类活性化合物丹酚酸A（SAA）的逆转机制。蛋白质免疫印迹法和实时定量聚合酶链反应（qRT-PCR）表明，凝溶胶蛋白2可能通过激活磷脂酰肌醇3激酶（PI3K）/Akt信号通路来抑制MCF-7/PTX细胞凋亡，从而介导紫杉醇耐药。MTT法和流式细胞术证实了SAA的逆转能力，其逆转指数高达9.1倍，增强了紫杉醇诱导的凋亡细胞毒性。此外，SAA有效阻止了凝溶胶蛋白2和三磷酸腺苷结合盒转运蛋白（ABC转运蛋白）包括P-糖蛋白（P-gp）、多药耐药相关蛋白1（MRP1）和乳腺癌耐药蛋白（BCRP）的上调，并对MCF-7/PTX细胞中的PI3K/Akt信号通路表现出抑制作用。综上所述，SAA可通过抑制凝溶胶蛋白2的表达来逆转紫杉醇耐药，其机制包括减弱PI3K/Akt通路激活和ABC转运蛋白上调。这些结果不仅为SAA在逆转紫杉醇耐药中的潜在应用提供了见解，从而提高乳腺癌化疗的敏感性，还突出了凝溶胶蛋白2在乳腺癌紫杉醇耐药发生中的潜在作用。
